The goal of the Urology Center's Program in the Division of Urology at the University of Pennsylvania Medical Center is to elucidate the molecular mechanisms for smooth muscle dysfunction in urinary bladder outlet obstruction. To accomplish this goal, we have developed a multi disciplinary research program that uses the clinical and basic science expertise in the Division of Urology, Depts. of Physiology and Pharmacology at the University of Pennsylvania Department of Physiology at the Allegheny University of Health Sciences, and the Department of Pediatric Urology at Children's Hospital of Philadelphia. The Program has three key elements: 1) the laboratories of four principal investigators that bring expertise in molecular biology, cellular biology, biochemistry, and physiology, 2) an Administrative Core (Core A) that will provide administrative and fiscal oversight, quality control for the research within individual projects, and will coordinate the research and interaction in the Urology Research Center, and 3) a Bladder Tissue Core (Core B) whose function is to serve as a resource for smooth muscle tissue from normal, obstructed and reversed urinary bladders from both rabbits and humans. In project 1, the investigators will analyze the calcium- induced calcium release and P2X cation channel expression to determine if the alteration in the contractility of the bladder smooth muscle during remodeling is due to changes in the mechanisms for Ca2+ uptake and release and/or changes in the P2X cation channel. In project 2, the investigators will determine if changes in the expression of myosin isoform and/or the regulatory mechanisms for actomyosin ATPase accounts for the alteration in the contractility of smooth muscle during bladder remodeling following outlet obstruction. In project 3, regulatory mechanisms, including Ca2+ sensitization, signaling pathways for active and passive force, shortening velocity and cross-bridge cycling following outlet obstruction will be studied. Thus, for the same bladder, following outlet molecular mechanisms for contractile dysfunction. The biochemical changes associated with compensation in the contractility of the detrusor in outlet obstruction will be determined. An understanding of the molecular mechanisms for entry of Ca2+ in the cytosol, activation of signaling pathways, calcium regulation of the actomyosin ATPase and force generation and shortening velocity is crucial for determining which regulatory steps are altered in the pathological state. Date from experiments on detrusor muscle tissue from the rabbit model for outlet obstruction and from patients with outlet obstruction would help to develop therapeutic agents targeted to correct the molecular events that are defective. Furthermore, we will be able to determine why some bladders fail to return to their normal contractility upon reversal of the obstruction in rabbits or removal of the prostate with BPH in humans.
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